Genetic variants of cytochrome P450 2C9 (CYP2C9) and vitamin K epoxide reductase (VKORC1) are known to influence warfarin dose, but the effect of other genes has not been fully elucidated. We ...genotyped 183 polymorphisms in 29 candidate genes in 1496 Swedish patients starting warfarin treatment, and tested for association with response. CYP2C9*2 and *3 explained 12% (P = 6.63 × 10−34) of the variation in warfarin dose, while a single VKORC1 SNP explained 30% (P = 9.82 × 10−100). No SNP outside the CYP2C gene cluster and VKORC1 regions was significantly associated with dose after correction for multiple testing. During initiation of therapy, homozygosity for CYP2C9 and VKORC1 variant alleles increased the risk of over-anticoagulation, hazard ratios 21.84 (95% CI 9.46; 50.42) and 4.56 (95% CI 2.85; 7.30), respectively. One of 8 patients with CYP2C9*3/*3 (12.5%) experienced severe bleeding during the first month compared with 0.27% of other patients (P = .066). A multiple regression model using the predictors CYP2C9, VKORC1, age, sex, and druginteractions explained 59% of the variance in warfarin dose, and 53% in an independent sample of 181 Swedish individuals. In conclusion, CYP2C9 and VKORC1 significantly influenced warfarin dose and predicted individuals predisposed to unstable anticoagulation. Our results strongly support that initiation of warfarin guided by pharmacogenetics would improve clinical outcome.
Recent genome-wide (GW) scans have identified several independent loci affecting human stature, but their contribution through the different skeletal components of height is still poorly understood. ...We carried out a genome-wide scan in 12,611 participants, followed by replication in an additional 7,187 individuals, and identified 17 genomic regions with GW-significant association with height. Of these, two are entirely novel (rs11809207 in CATSPER4, combined P-value = 6.1x10(-8) and rs910316 in TMED10, P-value = 1.4x10(-7)) and two had previously been described with weak statistical support (rs10472828 in NPR3, P-value = 3x10(-7) and rs849141 in JAZF1, P-value = 3.2x10(-11)). One locus (rs1182188 at GNA12) identifies the first height eQTL. We also assessed the contribution of height loci to the upper- (trunk) and lower-body (hip axis and femur) skeletal components of height. We find evidence for several loci associated with trunk length (including rs6570507 in GPR126, P-value = 4x10(-5) and rs6817306 in LCORL, P-value = 4x10(-4)), hip axis length (including rs6830062 at LCORL, P-value = 4.8x10(-4) and rs4911494 at UQCC, P-value = 1.9x10(-4)), and femur length (including rs710841 at PRKG2, P-value = 2.4x10(-5) and rs10946808 at HIST1H1D, P-value = 6.4x10(-6)). Finally, we used conditional analyses to explore a possible differential contribution of the height loci to these different skeletal size measurements. In addition to validating four novel loci controlling adult stature, our study represents the first effort to assess the contribution of genetic loci to three skeletal components of height. Further statistical tests in larger numbers of individuals will be required to verify if the height loci affect height preferentially through these subcomponents of height.
The number and volume of cells in the blood affect a wide range of disorders including cancer and cardiovascular, metabolic, infectious and immune conditions. We consider here the genetic variation ...in eight clinically relevant hematological parameters, including hemoglobin levels, red and white blood cell counts and platelet counts and volume. We describe common variants within 22 genetic loci reproducibly associated with these hematological parameters in 13,943 samples from six European population-based studies, including 6 associated with red blood cell parameters, 15 associated with platelet parameters and 1 associated with total white blood cell count. We further identified a long-range haplotype at 12q24 associated with coronary artery disease and myocardial infarction in 9,479 cases and 10,527 controls. We show that this haplotype demonstrates extensive disease pleiotropy, as it contains known risk loci for type 1 diabetes, hypertension and celiac disease and has been spread by a selective sweep specific to European and geographically nearby populations.
Despite great progress in identifying genetic variants that influence human disease, most inherited risk remains unexplained. A more complete understanding requires genome-wide studies that fully ...examine less common alleles in populations with a wide range of ancestry. To inform the design and interpretation of such studies, we genotyped 1.6 million common single nucleotide polymorphisms (SNPs) in 1,184 reference individuals from 11 global populations, and sequenced ten 100-kilobase regions in 692 of these individuals. This integrated data set of common and rare alleles, called 'HapMap 3', includes both SNPs and copy number polymorphisms (CNPs). We characterized population-specific differences among low-frequency variants, measured the improvement in imputation accuracy afforded by the larger reference panel, especially in imputing SNPs with a minor allele frequency of <or=5%, and demonstrated the feasibility of imputing newly discovered CNPs and SNPs. This expanded public resource of genome variants in global populations supports deeper interrogation of genomic variation and its role in human disease, and serves as a step towards a high-resolution map of the landscape of human genetic variation.
The reference sequence for each human chromosome provides the framework for understanding genome function, variation and evolution. Here we report the finished sequence and biological annotation of ...human chromosome 1. Chromosome 1 is gene-dense, with 3,141 genes and 991 pseudogenes, and many coding sequences overlap. Rearrangements and mutations of chromosome 1 are prevalent in cancer and many other diseases. Patterns of sequence variation reveal signals of recent selection in specific genes that may contribute to human fitness, and also in regions where no function is evident. Fine-scale recombination occurs in hotspots of varying intensity along the sequence, and is enriched near genes. These and other studies of human biology and disease encoded within chromosome 1 are made possible with the highly accurate annotated sequence, as part of the completed set of chromosome sequences that comprise the reference human genome.
There is increasing evidence that genome-wide association (GWA) studies represent a powerful approach to the identification of genes involved in common human diseases. We describe a joint GWA study ...(using the Affymetrix GeneChip 500K Mapping Array Set) undertaken in the British population, which has examined approximately 2,000 individuals for each of 7 major diseases and a shared set of approximately 3,000 controls. Case-control comparisons identified 24 independent association signals at P < 5 x 10(-7): 1 in bipolar disorder, 1 in coronary artery disease, 9 in Crohn's disease, 3 in rheumatoid arthritis, 7 in type 1 diabetes and 3 in type 2 diabetes. On the basis of prior findings and replication studies thus-far completed, almost all of these signals reflect genuine susceptibility effects. We observed association at many previously identified loci, and found compelling evidence that some loci confer risk for more than one of the diseases studied. Across all diseases, we identified a large number of further signals (including 58 loci with single-point P values between 10(-5) and 5 x 10(-7)) likely to yield additional susceptibility loci. The importance of appropriately large samples was confirmed by the modest effect sizes observed at most loci identified. This study thus represents a thorough validation of the GWA approach. It has also demonstrated that careful use of a shared control group represents a safe and effective approach to GWA analyses of multiple disease phenotypes; has generated a genome-wide genotype database for future studies of common diseases in the British population; and shown that, provided individuals with non-European ancestry are excluded, the extent of population stratification in the British population is generally modest. Our findings offer new avenues for exploring the pathophysiology of these important disorders. We anticipate that our data, results and software, which will be widely available to other investigators, will provide a powerful resource for human genetics research.
Organic carbon productivity and formation of hydrocarbon source rocks during the Early Precambrian was almost exclusively the product of the growth of microbial mats. Indirect evidence of microbial ...mats can be traced back to at least 2.6–2.7 Ga (Neoarchaean), with the earliest evidence of mat development in siliciclastic sediments coming from the 2.9 Ga (Mesoarchaean), predominantly marine sedimentary rocks of the Mozaan Group in South Africa. The earliest direct evidence for terrestrial microbial mats in siliciclastic sediments comes from the 2.75 Ga (Palaeoproterozoic) fluviolacustrine sediments of the Hardey Formation of the Pilbara craton in Western Australia. Well-preserved Proterozoic hydrocarbons provide valuable information about the early evolution of the biosphere. Eukaryotic steranes (biomarker for eukaryotic cells and, therefore, evolved forms of life) are present in the geological record from about 2.7 Ga, but they are not abundant or diverse within Archaean communities, which tend to be dominated by Archaea isoprenoids. Some hydrocarbons have been generated and migrated from Archaean organic-rich shales, but they were probably not of sufficient volume to be of commercial interest. The world's oldest significant hydrocarbon source rocks are Palaeoproterozoic in age and include the shungite deposits (2.0 Ga) in the Lake Onega region of Arctic Russia.
There is strong evidence of a global biospheric oxygenation event at c. 1300–1250 Ma (Mesoproterozoic) in conjunction with a first-order positive shift in the marine carbon isotope record. This is supported by the appearance of the oldest bedded marine gypsum deposits and of the earliest, unambiguously multicellular eukaryotes at this time. This oxygenation event probably played a significant role in supporting the more diverse eukaryotic communities preserved in the Neoproterozoic molecular record and provided the volume of organic material required to generate commercial volumes of hydrocarbons. Hydrocarbon source rocks of late Mesoproterozoic and Early Neoproterozoic age are widespread and include highly organic-rich shales deposited in restricted basinal settings adjacent to stromatolitic carbonate banks. By c. 850 Ma, the Neoproterozoic molecular record is dominated by hopanes from cyanobacteria with a significant abundance and diversity of eukaryotic steranes, including those of multicellular eukaryotes (red and green algae), as well as molecular evidence for heterotrophic protists. The most widespread hydrocarbon source rocks of mid to late Neoproterozoic age are commonly transgressive organic-rich black shales associated with inter-glacial and post-glacial phases of the Neoproterozoic global scale glaciations. The relative dominance of microbial mats in the contribution of organic matter as a source for hydrocarbon generation probably decreased significantly during the late Neoproterozoic and earliest Cambrian, perhaps as a result of the rapid growth of grazing metazoan communities or possibly as a result of changes in seawater chemistry and/or nutrient supply.
Precambrian and ‘Infracambrian’ petroleum systems are relatively abundant and widespread. The oldest live oil recovered to date is sourced from Mesoproterozoic rocks within the Velkerri Formation (Roper Group) of the McArthur Basin of northern Australia, dated at 1361 ± 21 Ma and 1417 ± 29 Ma (Re–Os dates) with at least the initial phase of oil generation and migration having taken place before 1280 Ma. However, the geologically oldest commercial production is currently from the somewhat younger mid to Late Neoproterozoic (Cryogenian–Ediacaran) petroleum systems of the Lena-Tunguska province in East Siberia and in southern China, from the latest Neoproterozoic to Early Cambrian Huqf Supergroup in Oman and, potentially in the near future, from the age-equivalent Mawar Supergroup in western India.
► Source rocks are relatively abundant and widespread in Precambrian successions. ► The oldest live oil recovered to date is sourced from Mesoproterozoic rocks. ► The oldest commercial production is from mid to Late Neoproterozoic successions. ► Precambrian source rocks are closely related to the evolution of life and the Earth's atmosphere. ► Cyanobacteria were the dominant source of organic matter during the Proterozoic.
Summary
The quantity of referrals to secondary care is increasing. That the quality of medical referrals is decreasing is a common allegation yet has rarely been assessed. We report a time‐limited, ...cross‐sectional survey evaluating cardiological referral information quality.
Referral letters (n = 218, excluding direct access pro formas) from GPs to the Cardiology Department at City Hospital, Birmingham, were collated and analysed over 2 months. A subset (n = 49) of these patients completed questionnaires assessing their knowledge and patient communication of the referral.
Information quality was poor (length, diagnosis, expectation, prior treatment and investigation) with almost half of all letters containing only outline symptomatic complaints without diagnosis. The majority of patients referred had not been investigated or treated in any way before referral. Despite lack of understanding of the reason for referral, typically the majority of patients expressed themselves as satisfied with the process.
Given most referrals are seen as appropriate, information exchange between secondary and primary care is crucial. By contrast, the standard of even basic clinical assessment communicated between primary care and secondary care was severely limited. The reason(s) why medical assessment is lacking are unclear but must be explored to give more support to primary care to complete basic medical task particularly if investment is to flow into this source.
The present study aimed to explore a new source of montmorillonite and to develop an extraction and purification protocol for its isolation from raw clay samples acquired from the Koh-e-Suleiman ...mountain range in Pakistan. The process involved the collection of raw clay from the source, identification and quantification of montmorillonite. Granulometric extraction and purification protocols increased the montmorillonite content from 21.8-25.1% in the raw clay to 90.1-93.9% after small-scale extraction and 85.33-89.33% on a larger scale. A techno-economic analysis highlighted the practicality and economic benefits of large-scale extraction for industrial applications. This study highlights the existence of a substantial new source of this valuable clay which is currently used across multiple industries including construction, pottery making, pharmaceuticals, cosmetics and engineering. It is intuitively expected that the large-scale extraction of the material will improve the economic condition of the region by providing employment opportunities to locals and may be a valuable resource for export.
Chromosome 9 is highly structurally polymorphic. It contains the largest autosomal block of heterochromatin, which is heteromorphic in 6-8% of humans, whereas pericentric inversions occur in more ...than 1% of the population. The finished euchromatic sequence of chromosome 9 comprises 109,044,351 base pairs and represents >99.6% of the region. Analysis of the sequence reveals many intra- and interchromosomal duplications, including segmental duplications adjacent to both the centromere and the large heterochromatic block. We have annotated 1,149 genes, including genes implicated in male-to-female sex reversal, cancer and neurodegenerative disease, and 426 pseudogenes. The chromosome contains the largest interferon gene cluster in the human genome. There is also a region of exceptionally high gene and G + C content including genes paralogous to those in the major histocompatibility complex. We have also detected recently duplicated genes that exhibit different rates of sequence divergence, presumably reflecting natural selection.
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